The process of designing potent and specific inhibitors has improved with the arrival of techniques for determining the three-dimensional structure of the enzyme to be inhibited. Usually a three-dimensional model of an enzyme is produced by the creation of a crystalline form of the purified enzyme which is then subjected to X-ray diffraction and analysis. While such procedures provide certain valuable information that can be used to design inhibitors, they suffer from a lack of knowledge about the amino acid residues critical for interaction with a substrate or a substrate mimic. In order to address these limitations, enzymes have more recently been co-crystallized with substrates, substrate mimics or known inhibitors of the enzyme's activity, thereby allowing the important interactions to be determined (see, for example, Mohammadi, et al., Science 276:955–960, 1997; Lee, et al., Biochemistry 36:13180–13186, 1997; Brzozowski, et al., Nature 389:753–758, 1997).
The peptidyl-prolyl cis-trans isomerases (PPIases), or rotamases, are a family of enzymes important in protein folding, assembly and transport. They act as catalysts to promote isomerization about the peptidyl-prolyl bond, which can have profound effects on protein function.
PPIases are divided into three classes, cyclophilins, FK-506 binding proteins (FKBPs) and the Pin1/parvulin class. While cyclophilins and FKBPs are distinguished by their ability to bind immunosuppressant molecules cyclosporin and FK-506, respectively, the Pin1/parvulin class binds neither of these immunosupressants and is structurally unrelated to the other two classes. Known members of the Pin1/parvulin class include Pins 1–3 (Lu, et al., Nature 380:544–547, 1996), Pin-L (Campbell, et al., Genomics 44:157–162, 1997), parvulin (Rahfeld, et al., FEBS Letts 352:180–184, 1994), dodo (Maleszka, et al., Proc Natl Acad Sci USA 93:447–451, 1996) and Ess1/Pft1 (Hanes, et al., Yeast 5:55–72, 1989; and Hani, et al., FEBS Letts 365:198–202, 1995).
Recent research suggests that members of the Pin1/parvulin class are essential modulators of the cell cycle, and mitosis in particular. Lu, et al., Nature 380:544–547, 1996 (incorporated by reference herein) reports that depletion of Pin1/Ess1 (a structural and functionally related protein to Pin1) in yeast or human cells induces mitotic arrest followed by apoptosis, indicating that enzymes in this class serve an essential function in cell division and proliferation.
The design of new, highly specific antimitotic agents represents an important need in the pharmaceutical industry. Such agents can serve as effective chemotherapeutic agents for the treatment of a variety of disorders characterized by inappropriate cell proliferation, including cancer and infectious diseases. The invention disclosed herein addresses this and related needs, as will become apparent upon review of the specification and appended claims.